In order to realize effective drug treatment for a variety of diseases and, in particular, for local lesions, it is necessary to achieve sufficient drug concentrations at local sites of action. Meanwhile, if the concentration of a drug increases in non-lesional tissue, the drug does not exhibit effective action at all, while on the other hand, it exhibits undesirable adverse effects in many cases. Therefore, drug delivery systems have been developed in order to deliver a relevant drug to a specific in vivo local site at which drug effects are expected to be exhibited so as to selectively increase the drug concentration at the site.
A method known as a means of drug delivery comprises preparing liposomes containing a drug or drug-encapsulated microcapsules, and allowing them to accumulate at a local site in the body for controlled-release of the drug at the site to cause the relevant local action. For such method, injectable preparation of leuprorelin, which is an antitumor agent (Non-Patent Document 1), injectable preparation of alprostadil, which is a blood circulation-improving agent (Non-Patent Document 2), and the like have been realized in practice. However, such examples of methods comprising allowing liposome or microcapsule preparations to accumulate at a local site in a body and to cause the relevant drug action are based on the enhanced permeability and retention (EPR) effect. This is the property that a drug preparation intravascularly administered leaks into extravascular tissue due to vascular fragility observed at the relevant site. In such method, drug accumulation efficiency depends on tissue properties of the local site. Therefore, it is difficult to freely deliver a drug to an arbitrary site in a body. In order to solve such problem, it has been attempted to allow microcapsule surfaces to present molecules specifically recognizing local tissues in a body, such as sugar chain recognizing molecules and antibodies recognizing surface antigens of target cells, so as to increase site accumulation specificity of the microcapsulated drug (Patent Documents 1 and 2). However, in cases in which a sugar chain or a cellular surface antigen that is specific to a target local site in a body at which a drug is expected to act has not been discovered, it is difficult to deliver the drug specifically to the local site.
Meanwhile, for example, a drug-coated stent has been well known and realized in practice as a drug delivery system using an indwelling medical device to be placed in vivo (Patent Document 3). Coronary artery stents coated with an immunosuppressant or an antiproliferative drug for controlled drug release can effectively prevent restenosis after stent implantation. Therefore, they were actively used for a while. However, it was revealed that coronary artery occlusion is induced with high frequency due to thrombosis in implanted stents, causing acute myocardial infarction and sudden death. Nevertheless, it is practically impossible to remove such implanted stents, resulting in a serious medical issue.
In addition, in medical practice, it is often required to change drug type, point in time of drug action induction, and effective period, for different reasons. For instance, in the case of a drug having therapeutic effects upon a lesion that requires to use an indwelling medical device, it is necessary to deliver a sufficient dose of the drug to the lesion during a period of high lesional activity. If the drug dose is reduced or drug administration is discontinued during a period in which the lesional activity is decreased, alleviation, disappearance, or prevention of adverse effects can be expected. Then, if the lesional activity increases again, it again becomes necessary to deliver a sufficient dose of the drug to the lesion. In order to meet such demands, a variety of medical devices for delivering a therapeutic drug to a local site in a body have been developed. However, regarding the supply of a drug to a desired target site during a continuous period, many problems remain unsolved.
Aneurysms are developed as a result of localized weakening of arterial walls due to excessive degradation or abnormal synthesis of the extracellular matrix constituting arterial walls followed by gradual expansion, resulting in rupture and leading to death. Before rupture, no substantial symptoms are observed. Therefore, an “effective aneurysm treatment” must involve the prevention of rupture in order to improve prognosis. The following are examples of aneurysm treatment methods that have been proved with efficacy to date: a method comprising replacing an aneurysm site with by an artificial blood vessel by surgery; and a method comprising inserting a stent graft (an artificial blood vessel) inside a blood vessel so as to block the bloodstream to the aneurysm. Such a stent graft is designed to extend through an aneurysm artery portion so as to reach normal vascular sites existing in front and to the rear of an aneurysm. Such a stent graft inserted inside the aneurysm portion expands by itself, tightly adheres to normal vascular sites located in front and to the rear of the aneurysm, and cuts off the hemodynamic load on the aneurysm to cause therapeutic effects. Stent grafting is an effective treatment method as long as complete cutting off of the hemodynamic load on an aneurysm can be achieved. However, the main problem is that the probability of the occurrence of incomplete cutting off of the hemodynamic load on an aneurysm exists. When arterial wall fragility and/or aneurysm expansion worsen after stent graft treatment, tight adhesion of a stent graft to the arterial wall becomes insufficient, and this could result in incomplete cutting off of the hemodynamic load on an aneurysm (endoleak) in some cases. Once the cutting off of the hemodynamic load on an aneurysm becomes incomplete, it is impossible for a stent graft to prevent the progression of aneurysm expansion and rupture. Therefore, it is important to completely maintain the tight adhesion of a stent graft to the arterial wall by effectively inhibiting pathological changes associated with aneurysm via drug treatment. At the same time, if regression of aneurysm can be realized via drug treatment, tight adhesion of a stent graft to the arterial wall and cutting off of the hemodynamic load on the aneurysm wall are completely possible to maintain in a more secure manner, resulting in significant improvement in outcomes of stent graft treatment.
JNK (c-Jun N-terminal kinase) inhibitors are drug that have been exclusively proven to induce aneurysm regression. Therefore, aneurysm regression via drug treatment has become probably possible in practice (Non-Patent Document 3). However, when such drugs are systemically administered, undesirable adverse effects could be observed. For example, known adverse effects of doxycycline are poor appetite, nausea, vomiting, diarrhea, rash, nephrotoxicity, and anemia. The use of antibiotics such as roxithromycin and tetracycline derivatives can induce widespread presence of antibiotic-resistant pathogens (Non-Patent Document 4). Also, regarding adverse effects of systemic administration of JNK inhibitors, there are concerns about adverse effects such as immunosuppression and liver dysfunction. In addition, hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors (statin), angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists, and the like have been known to cause adverse effects such as poor appetite, nausea, vomiting, diarrhea, rash, and excessive hypotension.
Patent Document 1: JP Patent Publication (Kokai) No. 2007-106752 A
Patent Document 2: JP Patent Publication (Kokai) No. 9-110722 A (1997)
Patent Document 3: JP Patent No. 3954616
Non-Patent Document 1: Yasuaki Ogawa et al., Chem Pharm Bull 36: 2576-2581, 1988
Non-Patent Document 2: Tetsuo Hamano et al., Clinical Report 20: 5145-5154, 1986
Non-Patent Document 3: Koichi Yoshimura et al., Nature Medicine 11: 1330, 2005
Non-Patent Document 4: Resistant Bacterial Infectious Diseases: Theory and Practice (Taiseikin Kansensho no Riron to Jissai) edited by Keiichi Hiramatsu, Medical Journal Sha, Co., Ltd. (2002)